Tommaso Gili

Regional brain atrophy and functional disconnection across Alzheimer's disease evolution

Objective To assess the contribution of regional grey matter (GM) atrophy and functional disconnection in determining the level of cognitive decline in patients with Alzheimers disease (AD) at different clinical stages. Methods Ten patients with amnesic mild cognitive impairment (a-MCI), 11 patients with probable AD and 10 healthy controls were recruited. T1 volumes were obtained from each subject and postprocessed according to an optimised voxel based morphometry protocol. Resting state functional MRI data were also collected from the same individuals and analysed to produce connectivity maps after identification of the default mode network (DMN) by independent component analysis. Results Compared with healthy controls, both AD and a-MCI patients showed a similar regional pattern of brain disconnection between the posterior cingulate cortex (PCC) and the medial prefrontal cortex and the rest of the brain. Conversely, the distribution of GM atrophy was significantly more restricted in a-MCI than in AD patients. Interestingly, the PCC showed reduced connectivity in a-MCI patients in the absence of GM atrophy, which was, in contrast, detectable at the stage of fully developed AD. Conclusions This study indicates that disconnection precedes GM atrophy in the PCC, which is a critical area of the DMN, and supports the hypothesis that GM atrophy in specific regions of AD brains likely reflects a long term effect of brain disconnection. In this context, our study indicates that GM atrophy in PCC accompanies the conversion from MCI to AD.

Anatomical connectivity mapping: A new tool to assess brain disconnection in Alzheimer's disease

Previous studies suggest that the clinical manifestations of Alzheimers disease (AD) are not only associated with regional gray matter damage but also with abnormal functional integration of different brain regions by disconnection mechanisms. A measure of anatomical connectivity (anatomical connectivity mapping or ACM) can be obtained by initiating diffusion tractography streamlines from all parenchymal voxels and then counting the number of streamlines passing through each voxel of the brain. In order to assess the potential of this parameter for the study of disconnection in AD, we computed it in a group of patients with AD (N=9), in 16 patients with amnestic mild cognitive impairment (a-MCI, which is considered the prodromal stage of AD) and in 12 healthy volunteers. All subjects had an MRI scan at 3T, and diffusion MRI data were analyzed to obtain fractional anisotropy (FA) and ACM. Two types of ACM maps, absolute count (ac-ACM) and normalized by brain size count (nc-ACM), were obtained. No between group differences in FA surviving correction for multiple comparison were found, while areas of both decreased (in the supramarginal gyrus) and increased (in the putamen) ACM were found in patients with AD. Similar results were obtained with ac-ACM and nc-ACM. ACM of the supramarginal gyrus was strongly associated with measures of short-term memory in healthy subjects. This study shows that ACM provides information that is complementary to that offered by FA and appears to be more sensitive than FA to brain changes in patients with AD. The increased ACM in the putamen was unexpected. Given the nature of ACM, an increase of this parameter may reflect a change in any of the areas connected to it. One intriguing possibility is that this increase of ACM in AD patients might reflect processes of brain plasticity driven by cholinesterase inhibitors.

The Thalamus and Brainstem Act As Key Hubs in Alterations of Human Brain Network Connectivity Induced by Mild Propofol Sedation

Despite their routine use during surgical procedures, no consensus has yet been reached on the precise mechanisms by which hypnotic anesthetic agents produce their effects. Molecular, animal and human studies have suggested disruption of thalamocortical communication as a key component of anesthetic action at the brain systems level. Here, we used the anesthetic agent, propofol, to modulate consciousness and to evaluate differences in the interactions of remote neural networks during altered consciousness. We investigated the effects of propofol, at a dose that produced mild sedation without loss of consciousness, on spontaneous cerebral activity of 15 healthy volunteers using functional magnetic resonance imaging (fMRI), exploiting oscillations (<0.1 Hz) in blood oxygenation level-dependent signal across functionally connected brain regions. We considered the data as a graph, or complex network of nodes and links, and used eigenvector centrality (EC) to characterize brain network properties. The EC mapping of fMRI data in healthy humans under propofol mild sedation demonstrated a decrease of centrality of the thalamus versus an increase of centrality within the pons of the brainstem, highlighting the important role of these two structures in regulating consciousness. Specifically, the decrease of thalamus centrality results from its disconnection from a widespread set of cortical and subcortical regions, while the increase of brainstem centrality may be a consequence of its increased influence, in the mildly sedated state, over a few highly central cortical regions key to the default mode network such as the posterior and anterior cingulate cortices.

Dielectric spectroscopy of erythrocyte cell suspensions. A comparison between Looyenga and Maxwell-Wagner-Hanai effective medium theory formulations

Abstract Two different dielectric models of biological cell suspensions have been used to describe the dielectric and conductive properties of the membrane of erythrocyte cells. The passive electrical properties of the cell membrane (the membrane permittivity e ′ and the membrane conductivity σ ) have been evaluated on the basis of the Maxwell–Wagner–Hanai and Looyenga mixture equations and the results have been compared in order to discuss the validity of the two models employed. Based on a simultaneous fit of the permittivity e ′ and the electrical conductivity σ , the Looyenga equation furnishes a better description of the dielectric behavior of an erythrocyte cell suspension over an extended frequency range, in comparison to the Maxwell–Wagner–Hanai equation.

Bilateral transcranial direct current stimulation language treatment enhances functional connectivity in the left hemisphere: Preliminary data from aphasia

Several studies have already shown that transcranial direct current stimulation (tDCS) is a useful tool for enhancing recovery in aphasia. However, no reports to date have investigated functional connectivity changes on cortical activity because of tDCS language treatment. Here, nine aphasic persons with articulatory disorders underwent an intensive language therapy in two different conditions: bilateral anodic stimulation over the left Brocas area and cathodic contralesional stimulation over the right homologue of Brocas area and a sham condition. The language treatment lasted 3 weeks (Monday to Friday, 15 sessions). In all patients, language measures were collected before (T0) and at the end of treatment (T15). Before and after each treatment condition (real vs. sham), each participant underwent a resting-state fMRI study. Results showed that, after real stimulation, patients exhibited the greatest recovery not only in terms of better accuracy in articulating the treated stimuli but also for untreated items on different tasks of the language test. Moreover, although after the sham condition connectivity changes were confined to the right brain hemisphere, real stimulation yielded to stronger functional connectivity increase in the left hemisphere. In conclusion, our data provide converging evidence from behavioral and functional imaging data that bilateral tDCS determines functional connectivity changes within the lesioned hemisphere, enhancing the language recovery process in stroke patients.

Images-based suppression of unwanted global signals in resting-state functional connectivity studies

Correlated fluctuations of low-frequency fMRI signal have been suggested to reflect functional connectivity among the involved regions. However, large-scale correlations are especially prone to spurious global modulations induced by coherent physiological noise. Cardiac and respiratory rhythms are the most offending component, and a tailored preprocessing is needed in order to reduce their impact. Several approaches have been proposed in the literature, generally based on the use of physiological recordings acquired during the functional scans, or on the extraction of the relevant information directly from the images. In this paper, the performances of the denoising approach based on general linear fitting of global signals of noninterest extracted from the functional scans were assessed. Results suggested that this approach is sufficiently accurate for the preprocessing of functional connectivity data.

Charged lipid monolayers at the air–solution interface: coupling to polyelectrolytes

Abstract The thermodynamic behaviour of mixed cationic–zwitterionic lipid mixtures dioleoyltrimethylammoniumpropane–dipalmitoylphosphatidylcholine (DOTAP–DPPC) at different mole fractions have been investigated by means of surface pressure measurements (Langmuir isotherms). Excess Gibbs energies of mixing have been calculated as a function of layer composition and surface pressure. Deviation from ideality evidences different molecular organisation of the two lipids, yielding the formation of cationic lipid domains in a zwitterionic lipid matrix. The stability of the mixed monolayer in the presence of both a simple electrolyte solution (NaCl) and a polyelectrolyte solution (NaPAA of different molecular weights) in the same charge ratio interval has been investigated and the influence of the polymer conformation briefly discussed.

L-DOPA PRELOADING INCREASES THE UPTAKE OF BOROPHENYLALANINE IN C6 GLIOMA RAT MODEL: A NEW STRATEGY TO IMPROVE BNCT EFFICACY

PURPOSE Boron neutron capture therapy (BNCT) is a radiotherapeutic modality based on (10)B(n,alpha)(7)Li reaction, for the treatment of malignant gliomas. One of the main limitations for BNCT effectiveness is the insufficient intake of (10)B nuclei in the tumor cells. This work was aimed at investigating the use of L-DOPA as a putative enhancer for (10)B-drug 4-dihydroxy-borylphenylalanine (BPA) uptake in the C6-glioma model. The investigation was first performed in vitro and then extended to the animal model. METHODS AND MATERIALS BPA accumulation in C6-glioma cells was assessed using radiowave dielectric spectroscopy, with and without L-DOPA preloading. Two L-DOPA incubation times (2 and 4 hours) were investigated, and the corresponding effects on BPA accumulation were quantified. C6-glioma cells were also implanted in the brain of 32 rats, and tumor growth was monitored by magnetic resonance imaging. Rats were assigned to two experimental branches: (1) BPA administration; (2) BPA administration after pretreatment with L-DOPA. All animals were sacrificed, and assessments of BPA concentrations in tumor tissue, normal brain, and blood samples were performed using high-performance liquid chromatography. RESULTS L-DOPA preloading induced a massive increase of BPA concentration in C6-glioma cells only after a 4-hour incubation. In the animal model, L-DOPA pretreatment produced a significantly higher accumulation of BPA in tumor tissue but not in normal brain and blood samples. CONCLUSIONS This study suggests the potential use of L-DOPA as enhancer for BPA accumulation in malignant gliomas eligible for BNCT. L-DOPA preloading effect is discussed in terms of membrane transport mechanisms.

Intrinsic Patterns of Coupling between Correlation and Amplitude of Low-Frequency fMRI Fluctuations Are Disrupted in Degenerative Dementia Mainly due to Functional Disconnection

Low frequency fluctuations (LFFs) of the BOLD signal are a major discovery in the study of the resting brain with functional magnetic resonance imaging (fMRI). Two fMRI-based measures, functional connectivity (FC), a measure of signal synchronicity, and the amplitude of LFFs (ALFF), a measure of signal periodicity, have been proved to be sensitive to changes induced by several neurological diseases, including degenerative dementia. In spite of the increasing use of these measures, whether and how they are related to each other remains to be elucidated. In this work we used voxel-wise FC and ALFF computed in different frequency bands (slow-5: 0.01-0.027 Hz; slow-4: 0.027-0.073 Hz; and full-band: 0.01-0.073 Hz), in order to assess their relationship in healthy elderly as well as the relevant changes induced by Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI). We found that in healthy elderly subjects FC and ALFF are positively correlated in anterior and posterior cingulate cortex (full-band, slow-4 and slow-5), temporal cortex (full-band and slow-5), and in a set of subcortical regions (full-band and slow-4). These correlation patterns between FC and ALFF were absent in either AD or MCI patients. Notably, the loss of correlation between FC and ALFF in the AD group was primarily due to changes in FC rather than in ALFF. Our results indicate that degenerative dementia is characterized by a loss of global connection rather than by a decrease of fluctuation amplitude.

Modeling the contribution of neuron-astrocyte cross talk to slow blood oxygenation level-dependent signal oscillations

A consistent and prominent feature of brain functional magnetic resonance imaging (fMRI) data is the presence of low-frequency (<0.1 Hz) fluctuations of the blood oxygenation level-dependent (BOLD) signal that are thought to reflect spontaneous neuronal activity. In this report we provide modeling evidence that cyclic physiological activation of astroglial cells produces similar BOLD oscillations through a mechanism mediated by intracellular Ca(2+) signaling. Specifically, neurotransmission induces pulses of Ca(2+) concentration in astrocytes, resulting in increased cerebral perfusion and neuroactive transmitter release by these cells (i.e., gliotransmission), which in turn stimulates neuronal activity. Noticeably, the level of neuron-astrocyte cross talk regulates the periodic behavior of the Ca(2+) wave-induced BOLD fluctuations. Our results suggest that the spontaneous ongoing activity of neuroglial networks is a potential source of the observed slow fMRI signal oscillations.